Will noninvasive screening for fibrosis/steatosis open Pandora’s box? Sharing the healthcare burden of state-of-the-art hepatology practice
Authors: Sarah Khorasani, Justin Boike, Andres Duarte-Rojo
Journal: Hepatology (2023)

With NAFLD growing as a leading cause of liver-related and cardiovascular morbidity and mortality, identifying patients most at risk for adverse outcomes is critical. Given the burden of disease and the impracticality of liver biopsy and hepatology specialty referral for all patients with suspected NAFLD, various noninvasive liver disease assessment (NILDA) strategies have emerged for risk stratification and triaging for an appropriate level of care.1 Current evidence supports liver fibrosis as a primary predictor of liver-related outcomes in patients with NAFLD. Recent clinical care pathways providing a framework for risk stratification and management of patients with NAFLD have been proposed, leveraging the accuracy of blood-based and imaging-based NILDA for the detection of liver fibrosis through tested algorithms.1 The objective is to identify patients at the highest risk of significant (F2) or advanced (F3) fibrosis and canalize them to liver-specialized care, before cirrhosis occurrence. A shortage in the hepatology workforce has been predicted for the upcoming years.2 This, along with the growing NAFLD incidence and increased awareness/screening, are expected to further stress the practice of hepatology. Given the already-burdened healthcare system and limited resource of specialized hepatology care, prioritization of referrals is necessary. Fibrosis-4 (FIB-4) can be calculated from basic laboratory values and is a lead point for most screening strategies. A sensitive cutoff for the FIB-4 score at 1.3 has been proposed to rule out F3 (>90% negative predictive value), whereas more specific cutoffs of 2.67 or 3.25 (66% and 73% positive predictive value, respectively) signal a high risk for F3 disease.3 These thresholds have been debated as a screening mechanism in the community setting.4 However, when tested outside of hepatology referral centers, FIB-4 had shown to have a lower-than-expected discriminatory accuracy, particularly at the extremes of age and when aiming to identify F2—a stage that would largely benefit from early interventions.5,6 As such, further risk stratification with liver stiffness measurement (LSM) has been proposed to prioritize referral of patients in need for an appointment with a liver specialist. The study by Vilar-Gomez and colleagues in this issue of Hepatology provides population-based data that suggest a more nuanced approach to risk stratification may be necessary in NAFLD patients.7 The authors demonstrated the association between fibrosis and all-cause (more specifically cardiovascular, malignancy, and “other”) mortality as determined by LSM from transient elastography. The manuscript also crucially described an independent association between the presence of steatosis and all-cause mortality. Using National Health and Nutrition Examination Survey (NHANES) data with a short average follow-up period of ∼2 years, it found a dose-dependent relationship between steatosis [defined by controlled-attenuated parameter (CAP)] and all-cause mortality, irrespective of fibrosis. These findings suggest patients with steatosis defined as a CAP ≥285 dB/m had rates of cardiovascular-related and malignancy-related mortality comparable to that of patients with cirrhosis. Importantly, FIB-4 was not found to be independently associated with mortality in the risk-adjusted analysis of this cohort of about 4200 participants. In clinical practice, it is relevant to define NILDA cutoffs that are tied to clinical outcomes. Presently, there is no consensus on CAP cutoffs for defining steatosis.8 Furthermore, the proposed cutoffs have been highly variable in previous reports ranging from 248 to 316 dB/m. Vilar-Gomez and colleagues utilized a threshold of 285 dB/m with prior validation in patients with biopsy-proven NAFLD. It is plausible that for screening people without known NAFLD, lower cutoff values will be needed (eg, 270 dB/m) to maximize sensitivity, although this possibility was not explored.9 Regardless of the CAP threshold, they demonstrated a dose-dependent relationship between CAP and mortality, further suggesting that steatosis exists on a spectrum of mild to severe disease rather than a phenomenon with discrete inflection points. This is similar to LDL cholesterol and its impact on the atherosclerotic cardiovascular risk disease model, although CAP’s dose-dependent relationship with mortality needs to be reproduced in more prospective studies. As for the LSM thresholds in this manuscript, authors utilized values of 9.7 kPa for F3–F4 and 13.6 kPa for F4, which were previously identified in 450 patients with biopsy-proven NASH. These single/optimal cutoff values agree with dual thresholds more recently reported in a large multicenter study and proposed in large-scale screening strategies, where an LSM <8 kPa rules out F3–F4 with a negative predictive value >90% (particularly for NAFLD and alcohol-related liver disease) and ≥12 kPa rules in F3–F4 with a positive predictive value >90%. Vilar-Gomez and colleagues also investigated the rule of 5 being proposed by the Baveno group, which establishes that for every 5 kPa between 10 and 25 kPa the risk for decompensation and liver-related death increases. They reported an excess of 15%–19% in overall mortality per each interval increase. Existing NAFLD/NASH risk stratification frameworks emphasize FIB-4 and LSM as the primary means of identifying patients at the highest risk for advanced fibrosis or liver-related complications and thus in need of prioritization for hepatology referral.1,10 These tools, however, do not consider steatosis as an independent contributor to liver and non–liver-related clinical outcomes, which the results of the current manuscript by Vilar-Gomez and colleagues bring to challenge. Given the findings described above, we propose a NILDA pathway to risk stratify NAFLD patients that incorporates liver steatosis. Patients identified as not being low risk by FIB-4 (ie, FIB-4 <1.3) should be referred for LSM and CAP assessment. Based on a patient’s level of risk, the pathway triages specialty care referral and proposes interventions to prevent progression of disease and minimize morbidity and mortality (Figure 1). Depending on the risk level, referral to hepatology or optimization of care within primary care would be advised, thus sharing the workload across specialties and practices. Importantly, the described limitations in FIB-4 as an initial screening tool strongly suggest the need for healthcare utilization comparative effectiveness studies (ie, FIB-4 vs. other blood-based NILDA as initial step). Repeat NILDA have been shown to improve their discriminative accuracy and should be considered for patients with fatty liver only staying within primary care.11 Regardless of fibrosis staging, there is a strong recommendation for cardiovascular risk reduction across these patients with fatty liver only. More importantly, steatosis may need to be considered a coronary artery disease risk factor like that of diabetes.Figure 1: Noninvasive liver disease assessment risk stratification tool for referral and care optimization in suspected NAFLD. Note: All patients with steatosis based on CAP (controlled attenuation parameter) scoring (or prior imaging) should be screened and/or advised for diabetes,hypertension, dyslipidemia, and cardiovascular risk. Lifestyle interventions, including weight loss through Mediterranean-based diet (favoring food with a low glycemic index) and incorporation of moderate-to-vigorous daily exercise should be recommended. Patients with diabetes and suspected NASH (non-alcoholic steatohepatitis) with LSM (liver stiffness measurement) >=8 kPa should consider glucagon-like-peptide 1 receptor agonists (GLP-1RA), a component of treatment given associated weight loss benefits and improvements in NASH. Subsequent diabetic therapies favor sodium glucose co-transporter 2 (SGLT2) inhibitors in non-cirrhotic NASH patients. 1MRE or magnetic resonance elastography is more accurate for detection of pre-cirrhotic stages of fibrosis but cannot substitute liver biopsy for diagnosis of NASH. 2CSPH (clinically significant portal hypertension) is likely present in patients with: a) platelet count (PLT) <110/nL plus LSM 15-19 kPa, or b) PLT <150/nL plus LSM 20-24 kPa, or LSM >=25 kPa. 3Ideally, patients should remain abstinent but <7 standard drinks/week might be safe. 4Favor supervised dietary intervention with monitoring of body composition and sarcopenia. 5Risk of hypoglycemia increases in cirrhosis, especially if decompensated (Child-Turcotte-Pugh or CTP >=8); beneficial effect of GLP-1RA or SGLT2 in this stage is unknown. EMR: electronic medical record; CLD: significant chronic liver disease; HTN, hypertension; LSM, liver stiffness measurement; PCP, primary care provider; SGLT2, sodium glucose co-transporter 2; VCTE: vibration-controlled transient elastography.Undoubtedly, further investigation into steatosis as an independent risk factor for cardiovascular mortality and malignancy is necessary before we can truly incorporate the degree of steatosis as measured by CAP into comprehensive NAFLD management schema. However, the data described above offer compelling evidence that NILDA are clinically useful both for measurements of fibrosis and of steatosis, and that risk stratification mechanisms are incomplete without inclusion of steatosis. These data also highlight the potential role of lifestyle and pharmacological interventions targeting steatosis alone on reducing liver and non–liver-related morbidity and mortality in patients with NAFLD.